Project 4: Project Summary/Abstract Physical activity is emerging as a potential non-pharmacological intervention to reduce the risk of developing symptomatic AD. However, there are several unresolved issues regarding the potential role of physical activity. First, the neurobiological mechanisms by which physical activity may be protective are unclear. While there is evidence from rodent studies that exercise-induced increase in trophic factors reduce AD pathology, enhance hippocampal neuroplasticity and improve hippocampal-dependent memory, this pathway has not been fully tested in humans. Second, there is limited understanding of the factors that contribute to individual differences in the effectiveness of physical activity. Third, the majority of studies have used self-report measures with variable evidence of reliability and validity, which could lead to biased estimation of effects. Lastly, the effect of physical activity on core AD pathology has been less examined with mixed findings in the literature. Project 4 will address these gaps and limitations by testing the mechanistic model supported by animal work in humans and determining factors that may moderate the beneficial effects of physical activity, both cross-sectionally and longitudinally. Aim 1 will test the hypothesis that higher levels of physical activity will be associated with benefits for neuronal/synaptic integrity and hence medial temporal lobe structure and episodic memory both directly by reduced amyloid deposition and tau phosphorylation (via increased trophic factors) and indirectly by mitigating the negative effects of AD pathology. Aim 2 will test the hypothesis that vascular health and the response of trophic factors to an acute bout of exercise moderate the effects of physical activity on AD biomarkers, medial temporal lobe structure and episodic memory. Exploratory Aim 3 will examine the role of stress exposure (Clinical Core) and reactivity, inflammation (Projects 1 & 2), and the gut microbiome (Project 3) in the effects of physical activity. Physical activity will be robustly characterized with objective measures of cardiorespiratory fitness and actigraphy-derived estimates of physical activity over 7 days. We will incorporate blood measures of trophic factors, CSF measures of neuronal integrity (Fluid Biomarker Core), structural MRI and DTI measures of medial temporal lobe structure (Project 1) as well as CSF and PET measures of AD biomarkers (Projects 1 & 2). Importantly, this Project represents a critical initial step in a line of research to determine the degree to which physical activity, directly and/or indirectly, influences the transition from cognitive normality to symptomatic AD.